Date Published: February 26, 2016
Publisher: Public Library of Science
Author(s): Jason W. Bennett, Anjali Yadava, Donna Tosh, Jetsumon Sattabongkot, Jack Komisar, Lisa A. Ware, William F. McCarthy, Jessica J. Cowden, Jason Regules, Michele D. Spring, Kristopher Paolino, Joshua D. Hartzell, James F. Cummings, Thomas L. Richie, Joanne Lumsden, Edwin Kamau, Jittawadee Murphy, Cynthia Lee, Falgunee Parekh, Ashley Birkett, Joe Cohen, W. Ripley Ballou, Mark E. Polhemus, Yannick F. Vanloubbeeck, Johan Vekemans, Christian F. Ockenhouse, Photini Sinnis. http://doi.org/10.1371/journal.pntd.0004423
Abstract: BackgroundA vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use.MethodsWe conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls.ResultsThe vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period.SignificanceThis trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.
Partial Text: Malaria is a devastating parasitic disease transmitted through the bite of infected Anopheles mosquitoes. Outside sub-Saharan Africa, Plasmodium vivax is the most prevalent of all human malarias with approximately 2.48 billion people at risk  and an estimated 16 million cases in 2013 (WHO World Malaria Report, 2014). Unlike Plasmodium falciparum, P. vivax produces liver stages (hypnozoites) that, initially dormant, can reactivate several weeks to months after the primary infection causing symptomatic disease [2,3]. This propensity to relapse stands as a significant barrier to efforts to eradicate this species of malaria . Additionally, P. vivax is increasingly reported as the causative agent of symptoms associated with severe malaria as well as chloroquine resistance [4–7]. A vaccine to prevent infection and disease caused by P. vivax is urgently needed to reduce morbidity of the disease and accelerate elimination of this parasite.
The development of a controlled human malaria infection challenge model to evaluate P. vivax vaccines is challenging and fraught with numerous technical obstacles. While P. falciparum has been adapted for use in CHMI primarily because of the ability to grow mature gametocytes that infect Anopheles mosquitoes to produce infectious stage sporozoites, the same methodology cannot be used for P. vivax. To date, P. vivax has proven refractory to continuous in vitro culture. Therefore, infection of permissive Anopheline mosquito species (i.e. An. dirus and An. albimanus)—that themselves are difficult to maintain and/or infect in insectaries—relies on the identification and consent of naturally-infected patients to present to medical treatment facilities to donate blood for initiating infection in mosquitoes. Nevertheless, the successful implementation of P. vivax CHMI previously reported in Colombia has opened the door to test vaccine efficacy by incorporating an infected mosquito challenge . In preparation for conducting a vaccine efficacy study we established a CHMI model for P. vivax at WRAIR, in collaboration with AFRIMS, using mosquitoes that were infected in Thailand (Chuang et al. in preparation.